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The major histocompatibility complex (MHC) plays a key role in immune defense, and the Mhc genes of cynomolgus macaque display a high degree of polymorphism. Based on their geographic distribution, different populations of cynomolgus macaques are recognized. Here we present the characterization of the Mhc class I and II repertoire of a large pedigreed group of cynomolgus macaques originating from the mainland north of the isthmus of Kra (N = 42). Segregation analyses resulted in the definition of 81 unreported Mafa-A/B/DRB/DQ/DP haplotypes, which include 32 previously unknown DRB regions. In addition, we report 13 newly defined Mafa-A/B/DRB/DQ/DP haplotypes in a group of cynomolgus macaques originating from the mainland south of the isthmus of Kra/Maritime Southeast Asia (N = 16). A relatively high level of sharing of Mafa-A (51%) and Mafa-B (40%) lineage groups is observed between the populations native to the north and the south of isthmus of Kra. At the allelic level, however, the Mafa-A/B haplotypes seem to be characteristic of a population. An overall comparison of all currently known data revealed that each geographic population has its own specific combinations of Mhc class I and II haplotypes. This illustrates the dynamic evolution of the cynomolgus macaque Mhc region, which was most likely generated by recombination and maintained by selection due to the differential pathogenic pressures encountered in different geographic areas. [ABSTRACT FROM AUTHOR]

The role of natural killer (NK) cells is tightly modulated by interactions of killer cell immunoglobulin-like receptors (KIR) with their ligands of the MHC class I family. Several characteristics of the KIR gene products are conserved in primate evolution, like the receptor structures and the variegated expression pattern. At the genomic level, however, the clusters encoding the KIR family display species-specific diversity, reflected by differential gene expansions and haplotype architecture. The human KIR cluster is extensively studied in large cohorts from various populations, which revealed two KIR haplotype groups, A and B, that represent more inhibitory and more activating functional profiles, respectively. So far, genomic KIR analyses in large outbred populations of non-human primate species are lacking. In this study, we roughly quadrupled the number of rhesus macaques studied for their KIR transcriptome (n = 298). Using segregation analysis, we defined 112 unique KIR region configurations, half of which display a more inhibitory profile, whereas the other half has a more activating potential. The frequencies and functional potential of these profiles might mirror the human KIR haplotype groups. However, whereas the human group A and B KIR haplotypes are confined to largely fixed organizations, the haplotypes in macaques feature highly variable gene content. Moreover, KIR homozygosity was hardly encountered in this panel of macaques. This study exhibits highly diverse haplotype architectures in humans and macaques, which nevertheless might have an equivalent effect on the modulation of NK cell activity. [ABSTRACT FROM AUTHOR]

The killer cell Ig-like receptors (KIR) modulate immune responses through interactions with MHC class I molecules. The KIR region in large cohorts of rhesus and cynomolgus macaque populations were characterized, and the experimental design enabled the definition of a considerable number of alleles (n = 576) and haplotypes, which are highly variable with regard to architecture. Although high levels of polymorphism were recorded, only a few alleles are shared between species and populations. The rapid evolution of allelic polymorphism, accumulated by point mutations, was further confirmed by the emergence of a novel KIR allele in a rhesus macaque family. In addition to allelic variation, abundant orthologous and species-specific KIR genes were identified, the latter of which are frequently generated by fusion events. The concerted action of both genetic mechanisms, in combination with differential selective pressures at the population level, resulted in the unparalleled rapid evolution of the KIR gene region in two closely related macaque species. The variation of the KIR gene repertoire at the species and population level might have an impact on the outcome of preclinical studies with macaque models. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex (MHC) is a highly polymorphic and polygenic genomic region that plays a crucial role in immune-related diseases. Given the need for comparative studies on the variability of immunologically important genes among wild populations and species, we investigated the allelic variation of MHC class II DRB among three congeneric true lemur species: the red-fronted lemur (Eulemur rufifrons), red-bellied lemur (Eulemur rubriventer), and black lemur (Eulemur macaco). We noninvasively collected hair and faecal samples from these species across different regions in Madagascar. We assessed DRB exon 2 polymorphism with a newly developed primer set, amplifying nearly all non-synonymous codons of the antigen-binding sites. We defined 26 DRB alleles from 45 individuals (17 alleles from E. rufifrons (N = 18); 5 from E. rubriventer (N = 7); and 4 from E. macaco (N = 20). All detected alleles are novel and show high levels of nucleotide (26.8%) and non-synonymous codon polymorphism (39.4%). In these lemur species, we found neither evidence of a duplication of DRB genes nor a sharing of alleles among sympatric groups or allopatric populations of the same species. The non-sharing of alleles may be the result of a geographical separation over a long time span and/or different pathogen selection pressures. We found dN/dS rates > 1 in the functionally important antigen recognition sites, providing evidence for balancing selection. Especially for small and isolated populations, quantifying and monitoring DRB variation are recommended to establish successful conservation plans that mitigate the possible loss of immunogenetic diversity in lemurs. [ABSTRACT FROM AUTHOR]

The killer-cell Ig-like receptors (KIRs) play a central role in the immune recognition in infection, pregnancy and transplantation through their interactions with MHC class I molecules. KIR genes display abundant copy number variation as well as high levels of polymorphism. As a result, it is challenging to characterize this structurally dynamic region. KIR haplotypes have been analyzed in different species using conventional characterization methods, such as Sanger sequencing and Roche/454 pyrosequencing. However, these methods are time-consuming and often failed to define complete haplotypes, or do not reach allele-level resolution. In addition, most analyses were performed on genomic DNA and thus were lacking substantial information about transcription and its corresponding modifications. In this paper, we present a single-molecule real-time sequencing approach, using Pacific Biosciences Sequel platform to characterize the KIR transcriptomes in human and rhesus macaque (Macaca mulatta) families. This high-resolution approach allowed the identification of novel Mamu-KIR alleles, the extension of reported allele sequences and the determination of human and macaque KIR haplotypes. In addition, multiple recombinant KIR genes were discovered, all located on contracted haplotypes, which were likely the result of chromosomal rearrangements. The relatively high number of contracted haplotypes discovered might be indicative of selection on small KIR repertoires and/or novel fusion gene products. This next-generation method provides an improved high-resolution characterization of the KIR cluster in humans and macaques, which eventually may aid in a better understanding and interpretation of KIR allele-associated diseases, as well as the immune response in transplantation and reproduction. [ABSTRACT FROM AUTHOR]